CYCLOOXYGENASE AND 5-LIPOXYGENASE INHIBITING HYDROXAMIC ACID DERIVATIVES

Abstract: The present invention is concerned with novel hydroxamic acid derivatives of formula (I) and their use in medical therapy, particularly in the prophylaxis or treatment of clinical conditions for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway is indicated. The invention also relates to pharmaceutical formulations and processes for the preparation of compounds according to the invention. In formula (I) Y is -C(Q)=C(Q')-((E)- or (Z)-) wherein Q and Q' are independently selected from hydrogen, C1-4 alkyl and halo, or Y is -CC-; R is C1-4 alkyl optionally substituted by fluoro; D is C1-4 alkyl, phenyl or -NR<1>R<2> (wherein R<1> and R<2> are independently selected from hydrogen, C1-4 alkyl, and phenyl); and ring A and ring B are each optionally substituted by a group or groups independently selected from halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -C(O)OR<3>, -C(O)R<3>, -C(O)NR<3>R<4>, -NR<3>R<4>, -NHCOR<3>, -NHCO2R<3>, -NHC(O)NR<3>R<4>, -NHSO2R<3>, -SO2NR<3>R<4> (wherein R<3> and R<4> are independently selected from hydrogen, C1-4 alkyl and phenyl), and -S(O)nR<5> (wherein n is an integer of from 0 to 2 and R<5> is C1-4 alkyl, C6-10 aryl (for example, phenyl or naphthyl), or C8-12 aralkyl).

Description: CYCLOOXYGENASE AND 5-LIPOXYGENASE INHIBITING HYDROXAMIC ACID DERIVATIVES . The present invention is concerned with hydroxamic acid derivatives having anti- inflammatory activity, with processes for their preparation, with pharmaceutical formulations containing said derivatives and with their use in medicine. European Patent Specification 0196184 describes hydroxamic acid derivatives having anti-inflammatory activity by virtue of their ability to inhibit the enzymes 5- lipoxygenase and cyclooxygenase in the mammalian arachidonic acid cascade. The compounds in question include those of formula OH Ar-Y'-N N COR! wherein, Y' is C2-10 alkenylene; R-l is Cj_4 alkyl, amino, C1-.4 alkylamino, or di-Cι-4 alkylamino; and Ar is phenyl optionally substituted by one or more substituents independently selected from: (i) Cj_4 alkyl (which may itself be optionally substituted by one or more halogen atoms), Cι _4 alkoxy, halo, nitro, amino, carboxy, C1-.4 alkoxycarbonyl, and hydroxy; (ii) phenyl optionally substituted by one or more substituents independently selected from those specified in (i). WO 90/12008, WO 92/10469, and WO 92/01682 also disclose compounds having lipoxygenase inhibitory activity. We have now discovered a class of compounds related to those of EP0196184, WO 90/12008, WO 92/10469, and WO 92/01682 having exceptionally good pharmacological and physical properties; particularly, with respect to their potent 5-lipoxygenase inhibitory activity, long duration of action and/or crystallinity. According to the present invention, therefore, there is provided a compound of formula (I) OH I wherein Y is -C(Q)=C(Q')- ((E)- or (Z)-) wherein Q and Q' are independently selected from hydrogen, C1-.4 alkyl and halo, or Y is -C≡C-; R is Cj_4 alkyl optionally substituted by fluoro; D is C\_Δ alkyl, phenyl or -N *R2 (wherein R* and R^ are independently selected from hydrogen, C ] _4 alkyl, and phenyl); and ring A and ring B are each optionally substituted by a group or groups independently selected from halo, cyano, nitro, hydroxy, C1-.4 alkyl, Cj_4 alkoxy, C1-.4 haloalkyl, C 1 . 4 haloalkoxy, -C(O)OR 3 , -C(O)R 3 , -C(O)NR 3 R 4 , -NR 3 R 4 , -NHCOR 3 , -NHCO 2 R 3 , -NHC(O) R 3 R 4 , -NHSO 2 R 3 , -SO 2 NR 3 R 4 (wherein R 3 and R 4 are independently selected from hydrogen, Ci .4 alkyl and phenyl), and -S(O) n R^ (wherein n is an integer of from 0 to 2 and R^ is C1-.4 alkyl, C . Q aryl (for example, phenyl or naphthyl), or Cg_ι aralkyl); provided that the compound of formula (I) is not: N-(3-[ 1 , 1 '-biphenyl]-4-yl- 1 -methyl-2-propynyl)-N-hydroxy-urea, N-(3 -[ 1 , 1 '-biphenyl]-4-yl- 1 -methyl-2-propynyl)-N-hydroxy-acetamide, (E)-N- [3 -(4'-Cyano-3 -biphenylyl)- 1 (S)-methyl-2-propenyl] acetohydroxamic acid, (E)-N-[3-(4'-Fluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, or (E)-N-[3-(4'-Chloro-3-biphenylyl)- 1 (S)-methyl-2-propenyl]acetohydroxamic acid; or a salt, solvate, or physiologically functional derivative thereof. It will be appreciated that compounds of formula (I) and their salts may exist in (R) or (S) enantiomeric forms. The present invention therefore includes within its scope each of the individual (R) and (S) enantiomers of the compounds of formula (I) and their salts substantially free, ie associated with less than 5%, of the other enantiomer and mixtures of such enantiomers in any proportions including racemic mixtures containing substantially equal amounts of the two enantiomers. For the avoidance of doubt, the present invention does not extend to a compound of formula: (E)-N-[3-(4'-Cyano-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, (E)-N-[3-(4'-Fluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid,and (E)-N-[3-(4 , -Chloro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; or to mixtures thereof with the corresponding (R) enantiomer wherein the (R) enantiomer constitutes less than 50% of the mixture. By the term halo is meant fluoro, chloro, bromo, or iodo; preferably fluoro or chloro; most preferably, fluoro. The terms alkyl and alkoxy include straight and branched alkyl and alkoxy groups respectively. The terms haloalkyl and haloalkoxy refer to alkyl and alkoxy groups respectively, in which one or more hydrogens has been replaced by halo. Y is preferably -C(Q)=C(Q')- (wherein either one of Q and Q' is methyl and the other is hydrogen, or Q and Q' are both hydrogen)or -C≡C-, more preferably Y is -CH=CH- or -C≡C-, and is most preferably -CH=CH- ; when Y is -C(Q)=C(Q')-, the double bond is preferably in the (E)- configuration. R is preferably Cj_4 alkyl in which one to three of the hydrogen atoms is optionally replaced by fluorine; more preferably Cj_4 alkyl; and is most preferably methyl. D is suitably C]_4 alkyl, phenyl, or H 2 , preferably Cj_4 alkyl (eg. methyl) or -NH 2 , more preferably C1-4 alkyl, and most preferably methyl. Ring A is suitably unsubstituted, or substituted by one to three groups independently selected from those listed in the definition of formula (I), for example, one or two substituents selected from halo, cyano, nitro, Cj_4 alkyl, C1-.4 alkoxy, Cj_4 haloalkyl, and Cι_4 haloalkoxy. Most preferably, Ring A has one substituent selected from halo, Cj_4 alkoxy (such as methoxy), and cyano in the 3- or 4-position relative to ring B or has two halo substituents in the 2- and 4-pόsitions relative to ring B. Ring B is suitably unsubstituted, or substituted by one or two groups independently selected from those listed in the definition of formula (I), for example, one or two substituents selected from halo, cyano, nitro, C1-.4 alkyl, C1-.4 alkoxy, C1-.4 haloalkyl, and Cι_4 haloalkoxy. Preferably, ring B is unsubstituted or substituted by one group selected from halo and cyano in the ortho position relative to ring A. Group Y is preferably attached to ring B at the 3- or 4-position relative to ring A, and most preferably at the 3 -position. A particular sub-group of compounds of formula (I) are those wherein: Y is -CH=CH- ((E)- or (Z)-), or -C≡C-; R is Cj_4 alkyl optionally substituted by fluoro; D is Cj_4 alkyl, phenyl or -NR1R2 (wherein R! and R^ are independently selected from hydrogen, C1-.4 alkyl, and phenyl); and ring A and ring B are each optionally substituted by a group or groups independently selected from halo, cyano, nitro, hydroxy, Cj_4 alkyl, C1-.4 alkoxy (said alkyl and alkoxy groups being optionally substituted by halo), -C(O)OR 3 -C(O)R 3 , -C(O) R 3 R 4 , -NR 3 R 4 , -NHCOR 3 , -NHCO R 3 , - HC(O) R 3 R 4 , - HSO 2 R 3 , - SO2NR R 4 (wherein R 3 and R 4 are independently selected from hydrogen, Cι_4 alkyl and phenyl), and -S(O) n R 5 (wherein n is an integer of from 0 to 2 and R^ is C1.4 alkyl, C6_IQ aryl (for example, phenyl or naphthyl), or Cg_ι 2 aralkyl); and salts, solvates and physiologically functional derivatives thereof. Of the aforementioned compounds of formula (I), those wherein Y is -CH=CH- ((E)- or (Z)-); and ring A and ring B are each optionally substituted by a group or groups independently selected from halo, nitro, hydroxy, C]_4 alkyl, Cj_4 alkoxy , C1-.4 haloalkyl, C ] _4 haloalkoxy, -C(O)OR 3 (wherein R 3 is as hereinbefore defined), and -NH 2 ; and salts, solvates and physiologically functional derivatives thereof; fall within the scope of EP 0196184 and represent a hitherto unrecognised sub-class having the advantageous properties previously referred to. In a further aspect, the present invention provides compounds of formula (I) wherein Y is -C(Q)=C(Q')- (wherein Q and Q' are as defined above for formula (I)); and D is C]_4 alkyl or phenyl; and salts, solvates and physiologically functional derivatives thereof; of which compounds wherein: ring A and/or ring B are/is substituted as described above for formula (I) with the proviso that at least one substituent is a group selected from cyano, -C(O)NR R 4 , -NHCOR 3 , -NHCO 2 R 3 , -NHC(O)NR 3 R 4 , -NHSO 2 R 3 , -SO 2 NR 3 R 4 (wherein R 3 and R 4 are as hereinbefore defined), -S(O) n R^ (wherein n and R^ are as hereinbefore defined), Cι_4 alkylamino, and di-Cj_4 alkylamino; form a further aspect of the present invention. Preferred compounds of formula (I) include those wherein: Y is -C(Q)=C(Q')- (wherein either one of Q and Q' is methyl and the other is hydrogen, or Q and Q' are both hydrogen) or -C≡C-; R is C1-.4 alkyl (such as methyl); D is Cj-4 alkyl (such as methyl), phenyl, or -NH 2 ; Ring A and ring B are optionally substituted by one or two substituents selected from halo, cyano, nitro, C1..4 alkyl, C1- alkoxy, C\.→ haloalkyl, and C]_4 haloalkoxy; and Y is attached to ring B at the 3- or 4- position relative to ring A and salts, solvates, and physiologically functional derivatives thereof Further preferred compounds of the invention include those wherein : Y is (E)- -CH=CH-; R is Cj_4 alkyl (such as methyl); D is Cj_4 alkyl (such as methyl); ring A and ring B are each optionally substituted by one or two groups independently selected from halo, C1-.4 alkoxy, and cyano, most suitably ring A has one substituent selected from halo, Cj_4 alkoxy, and cyano in the 3- or 4-position relative to ring B and ring B is unsubstituted or substituted by one group selected from halo and cyano in the ortho position relative to ring A; and Y is attached to ring B at the 3- or 4- position relative to ring A; and salts, solvates and physiologically functional derivatives thereof. Preferred compounds of formula (I) having excellent 5-lipoxygenase inhibitory activity include: (E)-N-[3-(4'-fluoro-3-biphenylyl)-l(R)-methyl-2-propenyl]-acetohydroxamic acid; N-[l-(4'-Fluoro-3-biphenylyl)but-l-yn-3(S)-yl]acetohydroxamic acid; (E)-N-[3'-Cyano-3-biphenylyl)but-l-en-3(S)-yl]acetohydroxamic acid; (E)-N-[3-(3,4'-difluoro-5-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3-(4'-Fluoro-4-biphenylyl)- 1 (S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3-(4'-Methoxy-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3-(3'-Fluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, (E)- 1 -[3-(4'-Cyano-3-biphenylyl)-l (R)-methyl-2-propenyl]- 1 -hydroxyurea; (E)- 1 - [( 1 R/S)-3 -(4-Biphenylyl)- 1 -methyl-2-propenyl]- 1 -hydroxyurea; (E)-N-[3-(2',4'-Difluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; and salts, solvates and physiologically functional derivatives thereof Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the ambit of the present invention, for use as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts and physiologically functional derivatives. Salts according to the invention include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D- glucamine, and salts with amino acids, such as arginine and lysine. Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p-toluenesulphonic, acids. By the term physiologically functional derivatives is meant chemical derivatives of compounds of formula (I) which have the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include compounds of formula (I) in which the hydroxyl of the hydroxamic acid functional group has been converted to a urethane, an alkyl ether, or an ester. As mentioned hereinbefore, compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof have use in the prophylaxis and treatment of clinical conditions for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway is indicated, as demonstrated hereinafter in the 5-lipoxygenase and cyclooxygenase inhibition assays in which representative compounds of the present invention have been shown to be active. For example, the ability of compounds of formula (I) to inhibit the lipoxygenase and cyclooxygenase mediated arachidonic acid metabolic pathways, renders them useful for the prophylaxis and treatment of spasmogenic conditions, allergic conditions, tumour formation, conditions involving blood platelet aggregation, and inflammatory conditions. Examples of spasmogenic conditions are those involving smooth muscle tissue, especially airway smooth muscle constriction such as asthma (including idiopathic bronchial asthma), bronchitis and arterial smooth muscle constriction such as coronary spasm (including that associated with myocardial infarction, which may or may not lead to left ventricular failure resulting in cardiac asthma), ischemia-induced myocardial injury, and cerebral spasm or 'stroke' (which may lead to central nervous pathophysiology). Other examples include bowel disease caused by abnormal colonic muscular contraction such as the conditions known as 'irritable bowel syndrome', 'spastic colon' and 'mucous colitis'. Examples of allergic conditions are extrinsic asthma, allergic skin diseases having a total or partial allergic origin, such as eczema, allergic bowel diseases (including coeliac disease), allergic eye conditions, such as hayfever (which may additionally or alternatively affect the upper respiratory tract), allergic rhinitis, and allergic conjunctivitis. Examples of tumours are skin neoplasms, mastocytoma and other forms of cellular proliferation, both benign and malignant. It is to be noted that the effectiveness of the present compounds in the prophylaxis and treatment of tumours may arise from properties in addition to 5-lipoxygenase inhibition which also inhibit cell proliferation. Examples of conditions involving blood platelet aggregation are those resulting from thrombosis, including 'strokes' having a total or partial thrombotic origin, coronary thrombosis, phlebitis and phlebothrombosis (the latter two conditions also possibly being associated with inflammation). Examples of inflammatory conditions are those of the lungs, joints, eyes, bowel, skin, and heart; particularly those associated with the infiltration of leucocytes into inflamed tissue. Inflammatory lung conditions include asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissue(s)). Inflammatory joint conditions include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions. Inflammatory eye conditions include uveitis (including iritis) and conjunctivitis. Inflammatory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis. Inflammatory skin diseases include those associated with cell proliferation, such as psoriasis, eczema and dermatitis (whether or not of allergic origin). Inflammatory conditions of the heart include coronary infarct damage. Other inflammatory conditions include tissue necrosis in chronic inflammation, endotoxin shock, smooth muscle proliferation disorders (for example, restenosis following angioplasty), and tissue rejection following transplant surgery. Accordingly, the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is indicated; which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. The present invention further provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, which clinical condition is a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition; which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. In the alternative, there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy; particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is indicated; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition. The amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. A suitable daily dose for a mammal suffering from, or likely to suffer from, any of the clinical conditions described hereinbefore is in the range O.lμg - 50mg of compound kilogram bodyweight. In the case of systemic administration, the daily dose is typically in the range 0.05 - 50mg of compound/kilogram bodyweight, the most preferred dosage being from 0.05 to 20mg/kg bodyweight, for example, from 0.1 to lOmg/kg, administered as two or three sub-doses daily. In the case of topical administration, e.g. to the skin or eye, a suitable dose is in the range O.lμg - lOOμg of base per kilogram, typically about O.lμg/kg. In the case of oral dosing for the prophylaxis or treatment of airway smooth muscle constriction, for example, in asthma or bronchitis, a suitable dose of the compound of the invention may be as specified in the preceding paragraph, but preferably is from 0.1 mg to lOmg of compound/kilogram bodyweight, the most preferred dosage being from 0.1 mg to 5mg/kg bodyweight. In the case of pulmonary administration, the dose is typically in the range 2μg - lOOmg/kg, preferably, from 5μg to 5mg kg, for example from 0.01 to 1 mg/kg. The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is indicated; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition. While it is possible for the compound of formula (I), or a salt, solvate, or physiologically functional derivative thereof to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. Hereinafter, the term "active ingredient" means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. The carrier or excipient must, of course, be compatible with the other ingredients in the formulation and must not be detrimental to the recipient. The active ingredient may comprise from 0.1% to 99.9% by weight of the formulation. Typical unit doses of a formulation according to the invention contain from O.Olmg to lg of the active ingredient. For topical administration, the active ingredient preferably constitutes from 1% to 2% by weight of the formulation, but the active ingredient may constitute as much as 10% w/w. Formulations suitable for nasal or buccal administration, typically contain from 0.1 to 20% w/w, for example, 2% w/w of the active ingredient. Formulations according to the invention include those in a form suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, topical, or nasal/buccal administration. The formulations of the invention may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. All such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Optionally, the particle size of the active ingredient may be reduced before formulation, for example, by micronisation. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form. Formulations according to the present invention which are suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution, suspension, or a microfine suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary, or paste. A tablet may be made by compressing or moulding the active ingredient, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a disintegrant, compression aid, binder, lubricant, inert diluent, and/or surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent. Formulations for rectal administration may be in the form of a suppository incoφorating the active ingredient and a carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration typically comprise a sterile aqueous or non-aqueous preparation such as an emulsion, suspension, or colloid of the active ingredient which is preferably isotonic with the blood of the recipient. Such formulations may also be freeze-dried and then reconstituted by addition of a sterile fluid shortly before administration. Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient, which latter may be in microcrystalline form, for example, an aqueous microcrystalline suspension. Liposomal formulations and biodegradable polymer systems may also be used, for example to present the active ingredient for parenteral, intra-articular and ophthalmic administration. Formulations suitable for topical administration include liquid and semi-liquid preparations such as liniments, lotions and applications; oil-in-water and water-in-oil emulsions such as creams, ointments and pastes; and solutions and suspensions such as drops. For example, for ophthalmic administration, the active ingredient may be presented as aqueous eye drops, for example, in the form of a 0.1 - 1.0% w/v solution. Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, or insufflators. For pulmonary administration via the mouth, the particle size of the powder or droplets is typically in the range 0.5 - lOμm, preferably 1 - 5μm, to ensure delivery into the bronchial tree. For nasal administration, a particle size in the range 10 - 500μm is preferred to ensure retention in the nasal cavity. Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150μl, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents. Nebulisers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas through a narrow venturi orifice, typically air or oxygen, or by means of ultrasonic agitation. Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the formulation, preferably less than 20% w/w. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavouring agents, volatile oils, buffering agents and surfactants. Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation. In addition to the aforementioned ingredients, formulations according to the invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, compression aids, disintegrants, surface active agents, thickeners, lubricants, preservatives, for example, methyl hydroxybenzoate, anti-oxidants and emulsifying agents. The compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from an antibiotic (for example, an anti-bacterial), anti-fungal, or anti-viral agent, an anti- histamine (particularly a peripherally-acting anti-histamine), or a non-steroidal anti- inflammatory drug (NSAID). The compounds of these combinations may be administered simultaneously, for example, in the same formulation or in separate formulations, or sequentially within a sufficiently short time interval to achieve the desired combined therapeutic effect. When the compounds are employed in the same formulation, a formulation according to the invention may contain, in addition to a compound of the invention, the further ingredient(s). According to a further aspect of the invention, there is provided a process for preparing the compounds of formula (I), or salts, solvates, or physiologically functional derivatives thereof which comprises reacting a compound of formula (II) wherein Y, R and the optional substituents on rings A and B are as defined for a compound of formula (I), with a suitable agent or agents to effect conversion of the N-hydrogen to an N-COD group, where D is (a) Cj_4 alkyl or phenyl, or (b) NR^R^ where R* and R^ are as hereinbefore defined; and optionally (i) separating the mixture of enantiomers so obtained and/or (ii) converting the compound of formula (I) so formed to a corresponding salt, solvate or physiologically functional derivative thereof. Conversion (a) is typically carried out by treating a compound of formula (II) with an acylating agent, for example, an appropriate anhydride or activated acid, such as an acid halide, for example, acetyl chloride. This reaction is suitably effected in an inert solvent, such as a halohydrocarbon, for example, dichloromethane, or an alkylbenzene, for example, toluene, at a temperature in the range -10°C to 150°C, for example 0-25° C in the presence of an organic base, such as a trialkylamine, for example, triethylamine. Any N,O-diacylated product of this reaction may be mono-O- deacylated, suitably by treatment with an inorganic base, for example, potassium carbonate, or by treatment with a suitable enzyme, such as a lipase. Conversion (b) is typically carried out by treating the compound of formula (II), or a salt thereof, (i) where Rl and R^ are to be hydrogen with a Group I cyanate, for example, potassium cyanate, in a non-polar solvent, such as tetrahydrofiiran (THF), in the presence of acid, such as a mineral acid, for example, dilute aqueous HC1, at a temperature in the range -10°C to 150°C, for example 0-25°C; (ii) where R 1 is to be Cj_4 alkyl or phenyl and R 2 is to be hydrogen, with the corresponding isocyanate R^NCO, in a suitable solvent, such as a halohydrocarbon, for example, dichloromethane, at a temperature in the range -10°C to 150°C, for example, 20-100°C; (iii) where R and R 2 are each to be C 1.4 alkyl or phenyl, with the corresponding carbamoyl halide, for example RlR 2 NCOCl, in an inert solvent, such as a halohydrocarbon, for example, dichloromethane, in the presence of base, such as an organic base, for example, pyridine, at a temperature in the range -10°C to 150°C, for example, 20-100°C. Where the compound of formula (II) is present as a single enantiomer, the compound of formula (I) may be obtained as the single enantiomer. Where the compound of formula (II) is present as a mixture of the (S) and (R) enantiomers, the compound of formula (I) may be obtained as a single enantiomer by : (i) separating the enantiomers obtained from the acylation reaction by any suitable method; (ii) effecting the mono-O- deacylation reaction by treatment with an enzyme capable of selectively reacting with one enantiomer, for example a lipase, to produce a mixture of the compound of formula (I) as a single enantiomer and the N,O-diacylated opposite enantiomer which can then be separated, for example by chromatography. The separated N,O-diacylated product of this reaction may then be mono-O-deacylated by any of the methods described above also to yield the compound of formula (I) as a single enantiomer. Compounds of formula (II) and salts thereof may be prepared from the corresponding compound of formula (III) wherein Y, R, and the optional substituents on rings A and B are as defined for a compound of formula (I), P' is a protecting group, such as an alkoxycarbonyl group, for example, -CO CH3, a cyclic ether, for example, tetrahydropyran, or t-butoxycarbonyl (Boc) and P" is a protecting group as described for P' or is hydrogen.. The conversion to a compound of formula (II) is suitably effected by acid or base hydrolysis as would be understood by the person skilled in the art. For example, where the -N(Boc)O(Boc) or -N(Boc)OH compound of formula (III) is used, the compound of formula (II), or a salt thereof, may be prepared by treatment with an acid, such as an arylsulphonic acid, for example, para-toluenesulphonic acid; in a non-polar solvent, for example, toluene; at a moderate temperature, suitably in the range 10-100°, for example, 50-60°C. The resulting salt of the compound of formula (II) may then optionally be hydrolysed to release the free base, for example, by chromatography on silica or by treatment with an inorganic base, such as a carbonate, for example, sodium carbonate. Compounds of formula (III) may be obtained either by: (i) reaction of the corresponding compound of formula (IN) H-Y-CHR-Ν(F)OF (IV) wherein Y and R are as hereinbefore defined and P' as defined above, with a compound of formula (V) wherein rings A and B are optionally substituted as described for formula (I) and L is a suitable leaving group, for example, a halogen, (typically bromo or iodo) or a substituted sulphonate, for example, trifluoromethanesulfbnate; typically at elevated temperature, for example, 50-150°C, in a polar solvent, for example, N,N-dimethylformamide, in the presence of a catalyst, such as palladium (II) acetate with tri(o-tolyl)phosphine, and a suitable base, such as a trialkylamine, for example, triethylamine; or (ii) reaction of a compound of formula (VI) wherein Y, R and the optional substituents on rings A and B are as defined for formula (I), with a compound of formula HN(P')OP' wherein P' is as defined for the compound of formula (III). This reaction may be effected under Mitsunobu conditions, for example in the presence of diethyl azodicarboxylate (DEAD) or di/ ' sopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPlvj); in a non-polar solvent, such as toluene; at low temperature, ie -20° to 50°C, for example in the region of 0°C. Alternatively, this reaction may be effected by activation of the compound of formula (VI), for example by esterification of the hydroxyl group, typically using an acid anhydride (eg. acetic anhydride) or an acid halide (e.g. chloroacetyl chloride); in the presence of a base (eg. 4-dimethylaminopyridine, DMAP); and a catalyst, for example, tetrakis(triphenylphosphine) palladium (O); in a non-polar solvent, such as tetrahydrofuran (THF); at elevated temperature, for example, 40-120°C. Compounds of formula (VI) may be prepared either : (i) by reduction of the corresponding compound of formula (VII) wherein Y, R, and the optional substituents on rings A and B are as defined for the compound of formula (I). The reduction may be done in such a way that a chiral alcohol of formula (VI) is obtained, for example, (a) by using a chiral inducing catalyst, suitably an oxazaborohdine CBS catalyst (E.J. Corey et al Tet Letters 31(5), 611 (1990)) with the reducing agent, suitably catechol borane in an inert solvent, such as a cyclic ether (eg.THF) or an alkylbenzene (eg. toluene) at low temperature, for example in the range -100°C to 50°C, or (b) by an enzymic reduction process. Alternatively, the reduction may be carried out to give the racemic alcohol of formula (VI) using conventional reducing agents of organic chemistry for example, treatment with sodium borohydride in a polar solvent, such as an alcoholic solvent, at low temperature, for example in the range -50°C to 30°C. If desired, the enantiomeric mixture of compounds of formula (VI) so obtained may be separated into the individual enantiomers by any suitable method, for example, by an enzymic resolution process, typically an enzyme catalysed acyl-transfer or hydrolysis reaction effected by treating the racemic compound of formula (VI) with an acyl donor, such as an enol ester (eg. vinyl acetate), an activated ester (eg. trifluoroethylbutyrate), or an acid anhydride (eg. succinic anhydride), in the presence of a suitable enzyme, such as a lipase, in an inert solvent, such as an aromatic solvent (eg. toluene), at non-extreme temperature, for example in the range -20°C to 60°C, or followed by treatment with a suitable enzyme capable of selectively hydrolising one acylated enantiomer, such as a lipase. The resulting enantiomers may then optionally be separated because one of them is present in acylated form, by any appropriate method, for example by chromatography. If desired, the unwanted enantiomer may be "recycled" for example by racemic deacylation, suitably by hydrolysis; or (ii) when Y is to be -C(Q)=C(Q')-, by reaction of the appropriate compound of formula (V) as defined above with a compound of formula (VIII) wherein Y, P', and R are as hereinbefore defined. This reaction may be carried out in the presence of a suitable catalyst system, for example, palladium (II) acetate/tri-(o-tolyl)phosphine, and a base, such as a trialkylamine, for example, triethylamine. Subsequent removal of the hydroxyl protecting group P' may be effected by any suitable method, such as hydrolysis, for example, acid hydrolysis. (iii) when Y is to be -CH=CH-, by reaction of the appropriate compound of formula (V) as defined above with crotonaldehyde (CH3CH=CHCHO) and then isomerising the resulting allylic alcohol to give the desired compound of formula (VI). The reaction with crotonaldehyde may be carried out typically by lithiation of the compound of formula (V), for example by treatment with butyl lithium at low temperature (suitably below -50°C) followed by treatment with the crotonaldehyde. The isomerisation may be carried out by treatment with acid, for example hydrochloric acid at moderate temperature. Where Y is to be -CH=CH-, the compound of formula (VII) may be prepared by reaction of the corresponding aldehyde of formula (IX) wherein the optional substituents on rings A and B are as defined for the compound of formula (I), with a compound of formula (X) wherein R is as defined for the compound of formula (I) and R 1 is C1 -.4 alkyl or, alternatively with acetone; in the presence of a base, such as sodium carbonate; in a polar solvent, such as THF, at a non-extreme temperature, for example -50° to 30°C. Compounds of formula (VIII) and HN(P')OP' may be prepared from the corresponding commercially available alcohol and hydroxylamine by standard protecting group chemistry. Compounds of formula (IX) may be prepared from compounds of formula (V) as defined above, typically by lithiation (for example with n-butyl lithium at low temperature, ie -100° to -20°C) followed by reaction with N,N-dimethylformamide (DMF). Compounds of formula (X) are commercially available or may be prepared by methods well known to the person skilled in the art or by methods readily available from standard chemical literature. Where Y is to be -C≡C-, the compound of formula (VTI) may be prepared from a compound of formula (XI) wherein the optional substituents on rings A and B are as defined for the compound of formula (I), by acylation with the appropriate carboxylic acid derivative, for example an ester or anhydride; in the presence of a base, for example, sodium hydroxide. Compounds of formula (XI) may be prepared by reaction of a compound of formula (V) with acetylene; typically, by lithiation of the acetylene with, for example, butyl lithium. Compounds of formula (IV) may be obtained by one or more of the methods described in EP 0384594. Compounds of formula (V) may be obtained commercially or prepared, for example, by coupling a compound of formula (XII) wherein ring A is substituted as defined for a compound of formula (I), or a suitably protected form thereof, with a compound of formula (XIII) wherein L is as defined above for formula (V) and L' is either the same as L or is a different leaving group as understood by a skilled person. This coupling may suitably be effected in the presence of a suitable catalyst, for example, tetrakis (triphenylphosphine) palladium (0) and an inorganic base, for example, sodium carbonate. Alternatively, compounds of formula (V) may be prepared by coupling a compound of formula (XIII) as hereinbefore defined with the appropriate organometallic reagent (for example, the appropriately substituted PhMgX or PhZnX, where X is a halogen) which may be prepared in situ from the corresponding halide by treatment with the metal (e.g. Mg or Zn). The coupling may be effected in an inert solvent, for example, THF, in the presence of a catalyst, for example, l,4-bis(diphenylphosphine)butane palladium (0) dichloride, palladium acetate, or tetrakistriphenyl phosphine palladium (0), at non- extreme temperature, for example 0-60°C. Enantiomeric compounds of the invention may be obtained (a) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods as described above, or preparing and separating suitable diastereoisomers, or (b) by direct synthesis from the appropriate chiral intermediates by the methods described above. Optional conversion of a compound of formula (I) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base. Optional conversion of a compound of formula (I) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art. According to a further aspect, the present invention provides novel intermediates for the preparation of compounds of formula (I), for example: (a) Compounds of formula (II) as defined above, or a salt thereof; particularly, a compound selected from: (E)-N-[ 1 -(4'-Fluoro-3-biphenylyl)but- 1 -en-3 (R)-yl]hydroxylamine; and N-[ 1 -(4'-Fluoro-3-biphenylyl)but- 1 -yn-3 (S)-yl]hydroxylamine; provided that the compound of formula (II) is not: (E)-N-[3-(4'-Cyano-3-biphenylyl-l(S)-methyl-2-propenyl]hydroxylamine; (E)-N-[3-(4'-Cyano-3-biphenylyl-l(R,S)-methyl-2-propenyl]hydroxylamine; (E)-N-[3-(4'-Fluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]hydroxylamine; (E)-N-[3 -(4'-Fluoro-3 -biphenylyl)- 1 (R, S)-methyl-2-propenyl]hydroxylamine; (E)-N-[3-(4'-Chloro-3-biphenylyl)- 1 (S)-methyl-2-propenyl]hydroxylamine; or (E)-N-[3 -(4'-Chloro-3 -biphenylyl)- 1 (R, S)-methyl-2-propenyl]hydroxylamine. (b) Compounds of formula (III) as defined above; particularly, a compound selected from: (E)-N,O-Bis(t-butoxycarbonyl)-N-[l-(4'-fluoro-3-biphenylyl)but-l-en-3(R)- yljhydroxylamine; and N, O-Bis(t-butoxycarbonyl)-N- [ 1 -(4'-fluoro-3 -biphenylyl)but- 1 -yn-3 (S)- yl]hydroxylamine; provided that the compound of formula (El) is not: (E)-N,O-Bis(t-butoxycarbonyl)-N-[3-(4'-cyano-3-biphenylyl)-l(S)-methyl-2- propenyl]hydroxylamine; (E)-N,O-Bis(t-butoxycarbonyl)-N-[3-(4'-cyano-3-biphenylyl)-l(R,S)-methyl-2- propenyljhydroxylamine; (E)-N, O-Bis(t-butoxycarbonyl)-N-[3 -(4'-fluoro-3 -biphenylyl)- 1 (S)-methyl-2- propenyljhydroxylamine; (E)-N,O-Bis(t-butoxycarbonyl)-N-[3-(4'-fluoro-3-biphenylyl)-l(R,S)-methyl-2- propenyl]hydroxylamine; (E)-N,O-Bis(t-butoxycarbonyl)-N-[3-(4'-chloro-3-biphenylyl)-l(S)-methyl-2- propenyl]hydroxylamine; or (E)-N,O-Bis(t-butoxycarbonyl)-N-[3-(4'-chloro-3-biphenylyl)-l(R,S)-methyl-2- propenyljhydroxylamine. For a better understanding of the invention, the following Examples are given by way of illustration. SYNTHETIC EXAMPLES Synthetic Example 1 Preparation of (E)-N-[3-(4'-fluoro-3-biphenylyl)-l(R -methyl-2-propenyl]- acetohydroxamic acid (a) 4-fluorophenylboronic acid A stirred solution of 4-fluorobromobenzene (105g) in dry tetrahydrofuran (THF) (500ml) under nitrogen was cooled to -70°C and then a 1.6M solution of butyllithium in hexane (375ml) was added slowly, keeping the temperature below -67°C. Stirring was then continued at -70°C for 10 minutes before pumping the mixture gradually into a stirred mixture of tri(isopropyl)borate (277ml) and dry THF (100ml) under nitrogen at -70°C. After the addition, the reaction mixture was stirred at -70°C for 10 minutes before being allowed to warm to ambient temperature. 2M aqueous hydrochloric acid (300ml) was then added and the reaction was stirred for a further 30 minutes. The reaction mixture was diluted with diethyl ether (125ml) and the resulting aqueous layer was separated and washed with diethyl ether (2x125ml). The combined ethereal solutions were washed with water and dried over MgSO4- Removal of the solvent gave the title compound as a cream solid (78.5g). (b) 3 -Bromo-4'-fluorobiphenyl To a stirred solution of 1,3-dibromobenzene (397g) in toluene (3.0 litres) under nitrogen, was added tetrakis (triphenylphosphine) palladium (0) (16.5g). A solution of the product from Example 1(a) (78.5g) in absolute ethanol (500ml) was then added followed by 2M aqueous Na 2 CO3 (561ml). The vigorously stirred reaction mixture was then refluxed for 11 hours under nitrogen. On cooling, the separated toluene layer was washed with water (2 x 500ml) and dried over MgSO4. Distillation afforded the title compound (85-90°C/0.1mbar). (c) (ΕVN. O-Bisf t-butoxycarbonylVN-f 1 -( 4'-fluoro-3-biphenylvDbut- 1 -en-3 fRV yl]hydroxylamine To a stirred solution of the product from Example 1(b) ( 7.53 g ) and N,O- bis(t-butoxycarbonyl)-N-but-l-en-3(R)-ylhydroxylamine, prepared as described in EP 0384594 (Synthetic Example 2) ( 8.61 g ) in dry N,N-dimethylformamide (30 ml ) and under a dry nitrogen atmosphere, was added triethylamine ( 6.72 g, Aldrich ) followed by tri(o-tolyl)phosphine ( 369 mg, Aldrich ) and palladium (II) acetate ( 135 mg, Lancaster ). The stirred mixture was heated at 100°C, with exclusion of light, for 6 hours then cooled to room temperature. Further tri(o-tolyl)phosphine ( 369 mg ) and palladium (II) acetate ( 135 mg ) were added and heating resumed for an additional 5 hours, then the reaction mixture was cooled to room temperature. The reaction mixture was poured into water ( 400 ml ) with stirring for 5 minutes, and then the mixture was extracted with diethyl ether ( 3 x 150 ml ). The extracts were combined, washed with water ( 3 x 200 ml ), dried over anhydrous magnesium sulphate, treated with charcoal and filtered. The filtrate was evaporated under reduced pressure to give an orange mobile oil ( 13.18 g ) from which the product ( 4,65 g ) and the mono-deprotected product ( 5.10 g ) were isolated by silica gel column chromatography, eluting with diethyl ether / petroleum ether bp 40-60°C ( 1 :2 ). (d) (EVN-[ 1 -(4'-Fluoro-3-biphenylyDbut- 1 -en-3(R)-yl]hydroxylamine A solution of the product from Example 1(c) ( 4.65 g ), the mono-deprotected hydroxylamine ( 5.10 g ) and toluene-4-sulphonic acid monohydrate ( 5.12 g, B.D.H. ) in toluene ( 100 ml ) was heated at 55°C under a nitrogen atmosphere for 3 hours then cooled to room temperature. The solution was diluted with diethyl ether ( 40 ml ) then left to stand at 4°C overnight. The solid so formed was filtered, washed with toluene / diethyl ether ( 1 : 1 ) and dried in vacuo to give the product as the tosylate salt ( 5.42 g ); mp 118 - 120°C. The salt was treated with excess saturated aqueous sodium hydrogen carbonate solution then the mixture was extracted with ethyl acetate ( 3 x 150 ml ). The combined extracts were washed with water ( 200 ml ), dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated under reduced pressure to give the product as a pale yellow, viscous oil ( 3.25 g ) which was used without further purification. (e) (E VO- Acetyl-N-[ 1 -f 4'-fluoro-3 -biphenylyl)but- 1 -en-3 (RVyl] acetohvdroxamate A stirred solution of the product from Example 1(d) ( 3.25 g ), pyridine ( 2.20 g ) and 4-(dimethylamino)pyridine ( 50 mg ) in dichloromethane ( 75 ml ) was cooled in an ice bath with the exclusion of moisture. A solution of acetyl chloride (2.18 g) in dichloromethane ( 20 ml ) was added drop wise over 20 minutes, then stirring was continued at 0°C for 60 minutes then at room temperature for 5 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between ether ( 400 ml ) and 2M hydrochloric acid ( 200 ml ), then the layers were separated. The ether layer was washed with saturated aqueous sodium hydrogen carbonate solution ( 200 ml ) then with water ( 200 ml ) and dried over anhydrous magnesium sulphate. Filtration and evaporation of the filtrate under reduced pressure gave the product as a pale yellow / orange oil (4.22 g ) which was used without further purification. (f) (EVN- [3 -(4'-fluoro-3 -biphenylylV 1 (RVmethyl-2-propenyll-acetohvdroxamic acid A solution of the product from Example 1(e) ( 4.22 g ), in methanol ( 75 ml ) was cooled in an ice bath with the exclusion of moisture, then anhydrous potassium carbonate ( 3.42 g ) was added with stirring at 0°C for 40 minutes. The reaction mixture was evaporated under reduced pressure and the residue treated with water (100 ml) followed by acidification with citric acid. The mixture was extracted with diethyl ether ( 3 x 150 ml ) and the combined extracts were then washed with water ( 2 x 150 ml ) and dried over anhydrous magnesium sulphate. The mixture was filtered and the filtrate evaporated under reduced pressure to give a pale orange / yellow, viscous oil from which the product ( 3.35 g ) was isolated as a pale yellow, viscous oil by silica gel column chromatography, eluting with diethyl ether. The oil was dissolved in ether and then the solution diluted with petroleum ether bp 40-60°C to give a faintly turbid solution which was left to stand at room temperature overnight. Filtration gave the racemate as a colourless solid ( 420 mg ); mp 132-133.5°C. The mother liquor was evaporated under reduced pressure and the residue was crystallised by trituration with diethyl ether / petroleum ether bp 40-60°C / ethyl acetate to give a solid which was then recrystallised from diethyl ether / petroleum ether bp 40-60°C ( 2 / 5 ) to give the product ( 1.62 g ) as a colourless solid; mp 114.5-116.5°C. 200 MHz 1H-NMR ( DMSOd 6 ) δ: 9.5 ( s, 1H, OH ), 7.9 - 7.2 ( m, 8H, ArH), 6.7 - 6.3 ( m, 2H, vinyl-H ), 5.30 - 5.05 ( m, 1H, methine-H ), 2.05 ( s, 3H, acetyl-H ), 1.35 - 1.25 ( d, 3H, methyl-H ). IR gave an intense peak at 1605 cm"l ( CO stretch ) FAB Mass Spectrometry gave ( M+l )+ at 300 and ( M+Na ) + at 322 22 5 23 [α] D " = + 168.52 0 [α] Hg546 = + 212.02° ( c = 1.0, ethanol ) Microanalysis: CιgH]gFNO % found ( calculated ) C 72.22 ( 72.07 ) H 6.06 ( 5,97 ) N 4.68 ( 5.08 ) Synthetic Example 2 Preparation of N-[l-(4'-Fluoro-3-biphenylyl but-l-yn-3(S)-yl1acetohydroxamic acid (a) N.O-BisCtert-butoxycarbonylVN- 1 - 3-bromophenyl)but- 1 -yn-3f SV yllhydroxylamine To a stirred mixture of l-bromo-3-iodobenzene (2.83g), N-(but-l- yn-3(S)-yl)- N,O-bis(t-butoxycarbonyl)hydroxylamine (2.85g) and triethylamine (60ml) under dry N 2 , was added bis(triphenylphosphino)palladium (II) dichloride (140mg) and copper (I) iodide (38mg). The reaction was shielded from light and stirring continued at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between diethyl ether (200ml) and water (100ml). The layers were separated and the ether layer was washed with 5% w/v aq. citric acid solution (100ml), then with water (100ml) and dried over anhydrous MgSO4. The mixture was filtered and the filtrate evaporated under reduced pressure to give a yellow oil (5.5g). The product was isolated as a colourless oil (4.0g) by passage through a short pad of silica gel, eluting with diethyl ether/40-60 o petroleum ether (1 :4). 1H NMR and FAB MS were consistent with the proposed structure. (b) N. O-Bis(t-butoxycarbonylVN-[ 1 -(4'-fluoro-3 -biphenylyHbut- 1 -vn-3 (S)→ yl " |hydroxylamine To a stirred solution of the product from part (a) (4.0g) in toluene (137ml) under N , was added tetrakis (triphenylphosphine)palladium (0) (291mg). When the catalyst had dissolved, a solution of 4-fluorophenylboronic acid (1.53g), in a minimum volume of absolute ethanol, was added, followed by 2M aq. Na 2 CO3 solution (10.9ml). The reaction mixture was heated under reflux with exclusion of light for 16 hours, then cooled. The reaction mixture was washed with water (2 x 100ml), dried over anhydrous MgSO4, filtered, and the filtrate was evaporated under reduced pressure. The pure product was isolated (3.28g) by passage through a short pad of silica gel eluting with diethyl ether/40-60° petroleum ether (1 :4). (c) N-f 1 -(4'-Fluoro-3-biphenylvDbut- 1 -yn-3 (S Vyllhydroxylamine A solution of the product from part (b) (3.28g) and toluene-4-sulphonic acid (2.05g) in methanol (75ml) was heated under reflux for 40 minutes, then cooled to room temperature. The reaction mixture was evaporated under reduced pressure and the residue was treated with saturated aq. NaHCO3 (75ml) and the mixture was extracted with ether (2 x 125ml). The combined extracts were washed with water (100ml), dried over anhydrous MgSO4, filtered and the filtrate was evaporated under reduced pressure to give an off- colourless oil (l*80g). (d) N-l " 1 -4'-Fluoro-3 -biphenylyl)but- 1 -yn-3 (s)-yl] acetohvdroxamic acid A stirred solution of the product from part (c) (1.80g), pyridine (1.23g), and 4-dimethylaminopyridine (50mg) in dichloromethane (75ml) was cooled in an ice/water bath with the exclusion of moisture. To the solution was added dropwise a solution of acetyl chloride (1.22g) in dichloromethane (10ml). After the addition, cooling was retained for 30 minutes, then the reaction mixture was allowed to warm to room temperature and left to stir overnight. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between 2M HCl (100ml) and diethyl ether (200ml). The organic phase was then washed successively with 2M HCl (50ml), saturated aq. NaHCO3 (100ml) and water (100ml). The ether solution was dried over anhydrous MgSO4 and the filtrate was evaporated under reduced pressure to give a colourless oil (2.25g). The oil was dissolved in methanol (50ml) and the solution cooled in ice/water with the exclusion of moisture. Anhydrous potassium carbonate (1.83g) was added then stirring continued at 0°C for 45 minutes. The reaction mixture was evaporated under reduced pressure, the residue treated with water (50ml) and then excess solid citric acid. The mixture was extracted with diethyl ether (200ml) and then the ther layer was washed with water (100ml), dried over anhydrous MgSO4, filtered and the filtrate was evaporated under reduced pressure to give a pale yellow viscous oil (1.93g). The oil was crystallised by trituration and recrystallised from diethyl ether/40-60 o petroleum ether to give the title product as fine colourless needles (1.54g); mp. 107-109°C. Synthetic Examples 3-7 The following compounds of formula (I) were prepared in a manner analogous to the method of Synthetic Example 1. The NMR, FAB MS and microanalysis of each compound were consistent with the proposed structure. 3) (E)-N-[3'-Cyano-3-biphenylyl)but-l-en-3(S)-yl]acetohydroxamic acid; Microanalysis: C 19 H 18 N 2 O 2 • 0.4H 2 O : C 72.67 (72.70),H 5.72(6.03), N 8.65(8.92). Prepared via: (E)-N,O-bis(t-butoxycarbonyl)-N-[3-(3'-cyano-3-biρhenylyl)-l(S)-methyl-2- propenyljhydroxylamine, (E)-N-[3 -(3 '-Cyano-3 -biphenylyl)- 1 (S)-methyl-2-ρropenyl]- hydroxylamine, and (E)-O-Acetyl-N-[3-(3'-cyano-3-biphenylyl)-l(S)-methyl-2-propenyl]- acetohydroxamate. 4) (E)-N-[3-(3,4'-difluoro-5-biphenylyl)-l(S)-methyl-2-propenyl]- acetohydroxamic acid; mp 88-90°C. Prepared via: 3-bromo-4',5-difluorobiphenyl (colourless oil), (S)-(E)-N-(t-butoxycarbonyl)-N-[3 -(4', 5-difluoro-3 -biphenylyl)- 1 -methylprop- 2-enyl]-hydroxylamine (yellow gum), (S)-(E)-N- [3 -(4', 5 -difluoro-3 -biphenylyl)- 1 -methylprop-2-enyl] hydroxylamine (colourless gum), and (S)-(E)-N-[3-(4', 5-difluoro-3-biphenylyl)- 1 -methylprop-2- enyl]acetohydroxamic acid (mp. 88-90°C) 5) (E)-N-[3-(4'-Fluoro-4-biphenylyl)- 1 (S)-methyl-2-propenyl]acetohydroxamic acid, mp 165-167°C; Prepared via: (E)-N,O-bis(t-butoxycarbonyl)-N-[3-(4'-fluoro-4-biphenylyl)-l(S)-methyl-2- propenyl]hydroxylamine,and (E)-N-[3-(4'-fluoro-4-biphenylyl)-l(S)-methyl-2-propenyl]hydroxylamine. 6) (E)-N-[3-(4'-Methoxy-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, 0.24 hydrate, mp 138-140°C. Prepared via: 3-bromo-4'-methoxy-biphenyl (mp. 47-49°C), (S)-(E)-N,O-bis(t-butoxycarbonyl)-N-[3-(4'-methoxy-3-biρhenylyl)-l- methylprop-2-enyl]hydroxylamine (yellow gum), (S)-(E)-N-[3-(4'-methoxy-3-biphenylyl)-l-methylprop-2-enyl]hydroxylamine (mp. 97-99°C), (S)-(E)-N,O-bisacetyl-N-[3-(4'-methoxy-3-biphenylyl)-l-methylprop-2-enyl]- hydroxylamine (mp. 73-75°C), and (S)-(E)-N-[3-(4'-methoxy-3-biphenylyl)l-methylprop-2-enyl]acetohydroxamic acid (mp. 138-140°C). 7) (E)-N-[3-(3'-Fluoro-3-biphenylyl)-l(S)-methyl-2- propenyl]acetohydroxamic acid, mp 72-76°C; Prepared via: (E)-N,O-bis(t-butoxycarbonyl)-N-[3-(3'-fluoro-3-biphenylyl)-l(S)-methylprop- 2-enyl]hydroxylamine (oil), (E)-N-[3-(3'-fluoro-3-biphenylyl)-l(S)-methylprop-2-enyl]-hydroxylamine (oil), and (E)-N,O-bis-acetyl-N-[3-(3'-fluoro-3-biphenylyl)-l(S)-methylprop-2-enyl]- hydroxylamine (oil). Synthetic Example 8 Preparation of CE)→ 1 -[3 -(4'-Cyano-3 -biphenylyl )- 1 (RVmethyl-2-propenyl " |- 1 - hydroxyurea. (a) 4-Cyanophenylboronic acid A cooled (-100°C), stirred solution / suspension of 4-bromobenzonitrile (9.10 g, Aldrich) in dry tetrahydrofuran (250 ml, Fluka) and under a dry nitrogen atmosphere, was treated dropwise over 20 minutes with a 1.6M solution of n- butyllithium in hexane (31.3 ml, Fluka). Stirring was continued at -100°C for a further 10 minutes and then the reaction mixture was transferred over 15 minutes into a cooled (-100°C), stirred mixture of tri(. iso-propyl)borate (23 c ml, Aldrich) and dry tetrahydrofuran(2 ml) under a dry nitrogen atmosphere. Stirring was continued at -100°C for a further 10 minutes then the temperature was allowed to rise to 20°C over 1.5 hours. To the reaction mixture was added 2M hydrochloric acid (50 ml) with vigorous stirring for 30 minutes and then the mixture was extracted with ether (150 ml). The organic layer was separated, washed with water (100 ml) and dried over anhydrous magnesium sulphate. The mixture was filtered and the filtrate evaporated under reduced pressure to yield a beige solid which, on recrystallisation from a minimum volume of boiling water, afforded cream needles (5.50 g); mp > 300°C. Microanalysis: C7H6BNO2 % found ( calculated ) C 56.96 (57.21) H 4.14 (4.12) N 9.42 (9.53) (b) 3 -Bromo-4'-cyanobiphenyl To a vigorously stirred solution of 1,3-dibromobenzene (26.49 g, Fluka) in toluene (610 ml) under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0), (1.30 g, Aldrich). Once all the solid had dissolved, a solution of 4-cyanophenylboronic acid (5.50 g) in a minimum volume of ethanol was added, followed by a 2M aqueous solution of sodium carbonate (41 ml). The vigorously stirred mixture was then heated under reflux for 19 hours with the exclusion of light. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and the layers were separated. The aqueous layer was extracted with fresh toluene (100 ml) and the organic layers were then combined, washed with water (2 x 250 ml), dried over anhydrous magnesium sulphate and filtered. Evaporation under reduced pressure gave a yellow oil which was purified by silica gel column chromatography, eluting firstly with petroleum ether bp 40- 60°C then with diethyl ether/petroleum ether bp 40-60°C (2/1) to give the pure product as a colourless solid (4.50 g) together with some slightly impure product as a pale yellow solid (2.44 g). IR gave an intense peak at 2224 cm" 1 (CN stretch) Mass Spectrometry El : (M+l) + at 257 and 259 Microanalysis: CπHsBrN % found (calculated) C 62.16 (60.49) H 3.22 (3.12) N 5.44 (5.43) (c) (ΕVN.O-Bis(t-butoxycarbonylVN-r 1 -(4'-cvano-3-biphenylvDbut- 1 -en-3(RVyl]- hydroxylamine To a stirred solution of the product from Example 8(b) ( 2.44 g ) and N,O- bis(t-butoxycarbonyl)-N-but-l-en-3(R)-ylhydroxylamine ( 2.71 g ) in dry N,N- dimethylformamide ( 10 ml ) and under a dry nitrogen atmosphere, was added triethylamine ( 2.12 g, Aldrich ) followed by tri(o-tolyl)phosphine ( 116 mg, Aldrich ) and palladium (II) acetate ( 43 mg, Lancaster ). The stirred mixture was heated at 100°C, with exclusion of light, for 10 hours then cooled to room temperature. The reaction mixture was poured into water ( 150 ml ) with stirring for 5 minutes, and then the mixture was extracted with ethyl acetate ( 3 x 75 ml ). The extracts were combined, washed with water ( 3 x 100 ml ), dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated under reduced pressure to give a tan, viscous oil ( 4.39 g ) which was used without further purification. (d) (Kl-N-r 1 -f4'-Cvano-3-biphenylvnbut- 1 -en-3fRV yllhvdroxylamine A solution of crude (E)-N,O-bis(t-butoxycarbonyl)-N-[l-(4'-cyano-3- biphenylyl)but-l-en-3(R)-yl]hydroxylamine ( 4.39 g ) and toluene-4-sulphonic acid monohydrate ( 2.25 g, B.D.H. ) in methanol ( 75 ml ) was heated under gentle reflux for 60 minutes then cooled to room temperature. The solution was evaporated under reduced pressure and the residue treated with saturated aqueous sodium hydrogen carbonate solution ( 40 ml ) then extracted into ethyl acetate ( 3 x 100 ml ). The combined extracts were washed with water ( 2 x 100 ml ), dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated under reduced pressure to give a tan gum ( 2.50 g ) which was used without further purification. (e) (EVN-r 1 -f 4'-Cvano-3-biρhenylynbut- 1 -en-3 (RVyll-N-hvdroxyurea A stirred solution of crude (E)-N-[l-(4'-cyano-3-biphenylyl)but-l-en-3(R)- yl]hydroxlamine ( 2.50 g ) in tetrahydrofuran ( 75 ml ) was cooled in an ice bath and then potassium cyanate ( 2.34 g ) was added followed by the dropwise addition of 2M hydrochloric acid ( 9.5 ml ) over 30 minutes. Stirring was continued at 0°C for a further 1.5 hours. The reaction mixture was diluted with ethyl acetate ( 150 ml ) and then washed with water ( 75 ml ), 2M hydrochloric acid ( 75ml ) and finally with water ( 2 x 75 ml ). The organic phase was dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated under reduced pressure to give a tan / orange gum from which the product ( 1.02 g ) was isolated as a pale yellow gum by silica gel column chromatography, eluting with ethyl acetate. Trituration with diethyl ether / petroleum ether bp 40-60°C / ethyl acetate gave a solid which was then recrystallised from ethyl acetate to give the product ( 375 mg ) as a cream solid; mp 154-155°C. 200 MHz 1H-NMR ( DMSOd 6 ) δ: 9.05 ( s, 1H, OH ), 8.0 - 7.4 (m, 8H, ArH), 6.7 - 6.3 ( m, 4H,vinyl-H + N-H ), 5.0 - 4.8 ( m, 1H, methine-H ), 2.05 ( s, 3H, acetyl-H ), 1.30 - 1.20 ( d, 3H, methyl-H ). IR gave intense peaks at 2230 cm -1 ( CN stretch ) and 1651 cm -1 ( CO stretch) 23 23 [α] D = + 47.170 [ ] Hg546 = + 58.59 0 ( c = 1.0, ethanol ) Synthetic Examples 9 and 10 B TIT ET RULE 26 The following compounds of formula (I) were prepared in a manner analogous to the method of Synthetic Example 1. The NMR, FAB MS and microanalysis of each compound were consistent with the proposed structure. 9) (E)- 1 -[(lR S)-3-(4-Biphenylyl)- 1 -methyl-2-propenyl]- 1 -hydroxyurea, mp 154.5-155°C; Microanalysis Cι 7 H 18 N 2 O 2 : C 72.44 (73.32), H 6.46 (6.43), N 9.79 (9.92). 10) (E)-N-[3-(2',4'-Difluoro-3-biphenylyl)-l(S)-methyl-2- propenyljacetohydroxamic acid, Microanalysis C 18 H 17 F 2 NO 2 • 0.34 H 2 O : C 66.66 (66.83), H 5.31 (5.51), N 4.23 (4.33). Prepared via: 2',4'-difluoro-3 -biphenylyl amine, 2',4'-difluoro-3-biphenylyl bromide, (S)-(E)-N-2-[4-(2',4 , -difluoro-3-biphenylyl)-but-3-enyl]-N-hydroxy-t-butyl- urethane, (S)-(E)-N-2-[4-(2',4'-difluoro-3-biphenylyl)-but-3-enyl] hydiOxylamine tosylate, (S)-(E)-N-2-[4-(2',4'-difluoro-3-biphenylyl)-but-3-enyl]-N-acetoxy-acetamide, and (S)-(E)-N-2-[4-(2',4'-difluoro-3-biphenylyl)-but-3-enyl]acetohydroxamic acid. Synthetic Example 11 Preparation of CR * S -(E)-N-2-[4-(4'-Fluoro-3-biphenylyl)pent-4-enyl1acetohydroxamic acid (a) 4'-Fluoro-3-biphenylylboronic acid 4'-Fluoro-3 -biphenylyl bromide (5.02g, 20mmol) was dissolved in dry THF (50ml) and the solution was stirred under dry nitrogen at -70°C. A solution of n-butyllitbium (1.6M in hexanes)(12.5ml, 20mmol) was added dropwise, keeping the internal temperature below -55°C. After the addition was complete, the solution was stirred at -70°C for 30 mins., then was added via a double-ended cannula, using nitrogen pressure, to a solution of tri-isopropyl borate (9.22ml, 40mmol) in dry THF (10ml) maintained at -70°C. The mixture was allowed to warm to room temperature, and treated with 2N HCl aq. (50ml) and stirred vigorously for 30 mins. The mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give 4.5g of crude product. Trituration under hexane afforded the title product as a colourless solid (2.07g, 48%yield). (b) (EV4-Bromopent-4-en-2-one This was prepared by the method of G. Buono, Synthesis 872 (1981)) (c) (E -4-(4'-Fluoro-3-biphenylyDpent-4-en-2-one The product from Example 11(b) (1.51g, 9.26mmol) (freshly purified by flash chromatography) was dissolved in THF (25ml), and the system was purged with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (0.214g, 2 mol%) was added and the mixture was stirred under nitrogen until the catalyst had dissolved. The product from Example 11(a) (4.0g, 9.26mmol) was added, followed by a solution of sodium carbonate (1.96g, 2eq.) in water (8ml). The mixture was heated at reflux under nitrogen overnight. It was then allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluted with ethyl acetate:hexane (15:85) to give the title compound as a colourless solid (1.39g, 59% yield) (d) f SV(EV4-('4'-Fluoro-3-biphenylvDpent-4-en-2-ol The product from Example 11(c) (1.39g, 5.47mmol) was stirred in methanol (30ml) at room temperature under nitrogen, and sodium borohydride (0.208g, 5.47mmol) was added portionwise over 15 mins. The mixture was stirred for 2 hours at room temperature, and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was separated and washed with semi-saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo to give the title product as a colourless amoφhous solid (1.32g). (e) (R.S)-(E)-N-2-[4-(4'-Fluoro-3-biphenylvnpent-4-enyll-N-(t- butoxycarbonyloxyVt-butylurethane The product from Example 11(d) (1.32g, 5.15mmol) was dissolved in dry THF, and triphenylphosphine (2.025g, 7.73mmol, 1.5eq.) and N,O-bis(t- butoxycarbonyl)hydroxylamine (1.260g, 5.41mmol, 1.05eq.) were added. The mixture was stirred at -5°C under dry nitrogen and treated with a solution of diethyl azodicarboxylate (1.345g, 7.73mmol, 1.5eq.) in dry THF (5ml) added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed in vacuo, and the residue dissolved in DCM, absorbed on silica and subjected to flash column chromatographic purification (ethyl acetate :hexane 10:90) to afford the slightly impure product (1.80g). (f) (R.SV(EV2-r4-r4'-Fluoro-3-biphenylyl)pent-4-enyl1hvdroxylaminep- toluenesulphonate The product from Example 11(e) (1.80g, 3.82mmol) was dissolved in dry toluene (10ml) and treated with p-toluenesulphonic acid monohydrate (0.799g, 4.20mmol, 1.1 eq.). The mixture was heated at 55-60°C under nitrogen for 2 hours, then the solvent was removed in vacuo. Trituration of the residue under diethyl ether afforded the title compound as a colourless solid (1.022g, 60% yield). (g) (R.S -(E -N-2-[4-r4 , -Fluoro-3-biphenylvnpent-4-envn-N-( ' acetoxy acetamide The product from Example 11(f) (l.Olg, 2.28mmol) was stirred in dry DCM (30ml) at 0°C under nitrogen, and dry pyridine (0.576g, 7.29mmol, 0.6ml, 3.2eq.) was added, followed by acetyl chloride (0.394g, 5.016mmol, 0.36ml, 2.2eq.). The mixture was allowed to warm to room temperature and was stirred overnight. The DCM was removed in vacuo, and the residue was partitioned between ethyl acetate and IN hydrochloric acid. The organic phase was separated, washed with IN hydrochloric acid, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (ethyl acetate :hexane 1:2) to yield the title compound as a colourless oil (0.445g, 55% yield). (h) (R * S)-(Ε VN-2- [4-(4'-Fluoro-3 -biphenylyl)pent-4-enyl] -acetohydroxamic acid The product from Example 11(g) (0.44g, 1.24mmol) was dissolved in methanol (20ml) and the solution was cooled in an ice/water bath. Anhydrous potassium carbonate (0.342g, 2.48mmol, 2eq.) was added, and the mixture was stirred for 90 mins. while being allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (ethyl acetate) to afford the title compound as a colourless resin (0.250g). N.m.r. spectrum (200MHz in DMSO-d 6 ) δ 1.35 (3H, d), 2.01 (3H, s), 2.10 (3H,s), 5.40 (1H, m), 5.95 (1H, d), 7.25-7.80 (8H,m), 9.55 (1H, br. s) Synthetic Examples 12 to 25 The following compounds of formula (I) were prepared in a manner analogous to the method of Synthetic Example 1. The NMR, FAB MS and microanalysis of each compound were consistent with the proposed structure. 12) (S)-N-[3-(4'-Fluoro-2'-methoxy-3-biphenylyl)-l-methylprop-2-enyl]- acetohydroxamic acid; Microanalysis Cι 9 H 20 FNO 3 • 0.2 H 2 O : C 68.57(68.53), H 6.00 (6.17), N 4.14 (4.20). 13 ) (E)-N-[3 -(4'-Fluoro-2-cyano-3 -biphenylyl)- 1 (S)-methyl-2-propenyl]- acetohydroxamic acid. 14) (E)-N-[ 1 -(3 '-Cyano-4'-fluoro-3-biphenylyl)but- 1 -en-3 (S)-yl]acetohydroxamic acid, mp 106.5-108.5 O C. 15) (E)-(S)-N-[3-(4'-Fluoro-3'-methyl-3-biphenylyl)-l-methylprop-2- enyl]acetohydroxamic, mp 105.5-107.5°C. 16) (S)-(E)-N-(l-Methyl-3-(3',4'-difluoro-3-biphenylyl)prop-2- enyl] acetohydroxamic acid; Microanalysis C!gH 17 F 2 NO2 • 0.6H 2 O : C 66.03 (65.88), H 5.58 (5.59), N 4.23 (4.27). 17) (S)-(E)-N-[3-(4 , -trifluoromethoxy-3-biphenylyl)-l-methylprop-2-enyl]- acetohydroxamic acid, mp 108-9°C. 18) (E)-(S)-N-[3-(4Tluoro-3-biphenylyl)-l-methylprop-2-enyl]-N-hydroxyurea, 0.25 hydrate, mp 138-139.5 0 C. 19) (S)-(E)-N-[ 1 -Methyl-3-(4'-trifluoromethyl-3-biphenylyl)-2-propenyl]- acetohydroxamic acid, mp 110-111°C. 20) (E)-N- [3 -(3 '-Nitro-3 -biphenylyl)- 1 (S)-methyl-2-propenyl] acetohydroxamic acid. 21) (E)-N-[3-(4-Biphenylyl)- 1 (S)-methyl-2-propenyl]acetohydroxamic acid, mp 159.5-161.5°C; 22) (E)-N-[3-(4'-Methyl-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, mp 166-168°C. 23) (E)-N-[(lR/S)-3-(3-Biphenylyl)-l-methyl-2-propenyl]acetohydroxamic acid, mp 108.5-109°C; 24) (E)- 1 -[( 1 R S)-3 -(3 -Biphenylyl)- 1 -methyl-2-propenyl]- 1 -hydroxyurea, mp 154.5-155°C; 25) (S)-N-[3-(4'-Cyano-3-biphenylyl)-l-methylprop-2-ynyl)acetohydroxamic acid, Microanalysis C 19 H 16 N 2 O 2 • 0.23 H 2 O : C 73.80 (73.97), H 5.20 (5.37), N 8.90 (9.08). Synthetic Example 26 Preparation of eR.SV(ΕVN-2-[ " 4-( " 4'-Fluoro-3-biphenylylV3-methylbut-3-enyll- acetohydroxamic acid (a) fR.SV3-Methylbut-3-en-2-ol Magnesium turnings (10.53g, 0.43mol) stirred in dry diethyl ether (5ml) under nitrogen were treated with a small crystal of iodine and 1ml of a solution of methyl iodide (26.76ml) in dry diethyl ether (80ml). When reaction had been initiated, the remaining methyl iodide solution was added dropwise at such a rate as to maintain gentle reflux (cooling in aa ice-water bath may be necessary). After the addition was complete, the mixture was heated under reflux for 30 mins., then cooled to 0°C and treated with a solution of 2- methylprop-2-enal (25g, 0.35mol) in dry diethyl ether ( 85ml) added dropwise. The mixture was stirred at room temperature overnight, then cooled in an ice- water bath. Saturated ammonium chloride aq. (85ml) was added dropwise with vigorous stirring. The organic phase was separated, and the aqueous phase was extracted with diethyl ether (2x200ml). The organic extracts were combined, dried over anhydrous magnesium sulphate and filtered. The ether was removed by fractional distillation at atmospheric pressure (under nitrogen) until the volume had been reduced to 50ml. Examination of the residue by nmr spectroscopy showed that it consisted of a mixture of the title compound and diethyl ether in the ratio 1:1.64 (yield: 65.17g). (b) (R.S)-N.O-bis(t-butyloxycarbonylVN-2-(3-methylbut-3-enyl) hydroxylamine A solution of 3-methylbut-3-en-2-ol (2.5g, 29mmol) in dry diethyl ether (from stage (i)) was dissolved in dry THF (100ml), and the solution was stirred under nitrogen at room temperature. Triphenylphosphine (11.42g, 43.6mmol, 1.5eq.) and N,O-bis(t-butyloxycarbonyl)hydroxylamine (7.10g, 30.45mmol, 1.05eq.) were added. The resulting solution was cooled to -5°C, and treated with a solution of diethyl azodicarboxylate (7.58g, 43.6mmol, 1.5eq.) in dry THF (20ml) added dropwise, maintaining the internal temperature at -5°C. The mixture was allowed to warm to room temperature and left over the weekend. The solvents were removed in vacuo, and the residue was subjected to flash column chromatography on silica, hexane then 5:95 ethyl acetate:hexane as eluent to afford the title compound as a colourless oil (1.89g). (c) rR.SV(EVN-2-| ' 4-( ' 4'-Fluoro-3-biphenylvn-3-methylbut-3-enyll-N-rhvdroxyVt- butylurethane A mixture of 4'-fluoro-3 -biphenylyl bromide (1.225g, 5mmol), the product from Example 26(b) (1.806g, όmmol), triethylamine (1.53ml, l lmmol, 2.2eq.) and bis[(tri-o-tolyl)phosphine] palladium(II) chloride (0.196g, 0.25mmol, 5 mol%) in DMF (40ml) stirred under nitrogen was heated at 100-110°C overnight. The mixture was cooled to room temperature,diluted with ethyl acetate to 300ml, filtered through celite, washed with 5% citric acid aq. then with saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica, 10:90 ethyl acetate: hexane eluent to yield the title compound (0.88g). (d) (R.SV(EVN-2-[4-(4'-Fluoro-3-biphenylylV3-methylbut-3-enyll hydroxylamine The product from Example 26(c) (0.87g,2.345mmol) was dissolved in dry toluene (6ml) and p-toluenesulphonic acid (0.475g, 2.5mmol, 1.05eq.) was added. The mixture was heated, with stirring, at 50-60°C under nitrogen for 1.5 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica, 4:96 methanol: dichloromethane eluent to afford the title compound (0.49 lg, 77%). (e) fR.SV(ΕVN-2-r4-r4'-Fluoro-3-biphenylylV3-methylbut-3-enyl ' |-N-racetoxyV acetamide The product from Example 26(d) (0.485g, 1.79mmol) was dissolved in DCM (25ml), and the solution was stirred in an ice-water bath under nitrogen. Pyridine (0.32ml, 3.93mmol, 2.2eq.) was added, followed by acetyl chloride (0.28ml, 3.93mmol, 2.2eq.). The reaction mixture was then allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and IN hydrochloric acid. The organic phase was separated, washed with IN hydrochloric acid, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (ethyl acetate: hexane 1 :2) to yield the title compound as a colourless oil (0.479g, 75% yield). (f) (R.SVrEVN-2-r4-f4'-Fluoro-3-biphenylvn-3-methylbut-3-enyl1- acetohvdroxamic acid The product from Example 26(e) (0.47g, 1.324mmol) was dissolved in methanol (20ml) and the solution was stirred under nitrogen at 0°C. Anhydrous potassium carbonate (0.365g, 2.648mmol, 2eq.) was added, and the mixture was stirred at 0°C for 2 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, then with semi-saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (ethyl acetate) to afford the title compound as a colourless resin (0.280g). N.m.r. spectrum (200MHz in DMSO-d 6 ) δ 1.34 (3H, d), 1.85 (3H, s), 2.05 (3H, s), 5.07 (1H, m), 6.47 (1H, br.s), 7.24-7.76 (8H, m), 9.38 (1H, br.s). Synthetic Examples 27 to 42 The following compounds of formula (I) were prepared in a manner analogous to the method of Synthetic Example 1. The NMR, FAB MS and microanalysis of each compound were consistent with the proposed structure. 27) (E)-N-[l-(4'-Fluoro-3-biphenylyl)but-l-en-3(R,S)-yl]acetohydroxamic acid, mp 134-136°C. 28) (E)-N-[l-(4'-Fluoro-3-biphenylyl)but-l-en-3(R,S)-yl]-N-hydroxyurea, mp 159.5-160.5. 29) (R,S)-N-Benzoyl-N-[3-(4'-fluoro-3-biphenylyl)-l-methylprop-2- enyljhydroxamic acid; mp 130°C (0.14 hydrate). 30) (E)-N-[3-(4'-Fluoro-2'-cyano-3-biphenylyl)-l(S)-methyl-2-propenyl] acetohydroxamic acid. 31) Ethyl 3'-[3-(N-hydroxyacetamido)-(3S)-but-l-enyl]biphenyl-4-carboxylate, Microanalysis C 21 H 23 NO 4 : C 71.24 (71.37), H 6.62 (6.56), N 3.94 (3.96). 32) (S)-(E)-N-[3-(4'-Isopropylsulphonyl-3-biphenylyl)-l-methylprop-2-enyl]- acetohydroxamic acid, mp 133-4°C. 33) (S)-N- [3 -(4'- Acetyl-3 -biphenylyl)- 1 -methyl- 1 -prop-2-enyl] acetohydroxamic acid, Microanalysis C 20 H 21 NO 3 : C 74.19 (74.28), H 6.46 (6.55), N 4.28 (4.33). 34) (E)-N-[3-(4'-Dimethylaminosulphonyl-3-biphenylyl)-l(S)-methyl-2-propenyl]- acetohydroxamic acid, hemihydrate, mp 83-87°C. 35) (E)-N-[3-(4'-Hydroxy-3-biphenylyl)-l(R,S)-methyl-2- propenyljacetohydroxamic acid. 36) (S)-N-[3 -(4'-Carbamoyl-3 -biphenylyl)- 1 -methylprop-2-enyl]acetohydroxamic acid. 37) (E)-N-[3-(4'-Ethylsulphonyl-3-biρhenylyl)-l(S)-methyl-2-propenyl]aceto- hydroxamic acid, mp 129-131°C. 38) (E)-N-[ 1 (S)-methyl-3-(4'-methylsulphonyl-3-biρhenylyl)-2-proρenyl]- acetohydroxamic acid, mp 163°C; 39) (E)-N-[3-(4-Biphenylyl)-l(R/S)-methyl-2-propenyl]acetohydroxamic acid, mp 163.5-165.5°C; 40) (S)-(E)-N- { 1 -methyl-3 -[3 '-(N,N-dimethylcarbamido)-3 -biphenylyl]prop-2- enyl} acetohydroxamic acid, 0.4 hydrate, mp 98°C (foams). 41) (S)-(E)-N-{ l-methyl-3-[(3'-methanesulphonamido)-3-biphenylyl]prop-2-enyl} acetohydroxamic acid, dihydrate, mp 64-6°C. 42) (S)-(E)-N-[l-methyl-3-(3'-Acetamido-3-biphenylyl)prop-2- enyl]acetohydroxamic acid hemihydrate, mp 157-160°C. PHARMACEUTICAL FORMULATION EXAMPLES The "active ingredient" in the following formulations is as defined above; preferably one of the compounds of Synthetic Examples 1 to 42. Example A: Oral Tablet (i) Per tablet Active Ingredient 50.0 mg Lactose 61.0 mg Sodium Starch Glycollate 10.0 mg Povidone 3.0 mg Magnesium Stearate 1.0 mg Mix together the active ingredient, lactose and sodium starch glycollate . Granulate the powders using a solution of povidone in purified water. Dry the granules, add the magnesium stearate and compress to produce tablets. Example B: Ointment Active Ingredient 1.0 g White Soft Paraffin to 100.0 g Disperse the active ingredient in a small volume of the vehicle. Gradually incoφorate this into the bulk to produce a smooth, homogeneous product. Fill into collapsible metal tubes. Example C: Cream for topical use Active Ingredient 1.0 g Polawax GP 200 20.0 g Lanolin Anhydrous 2.0 g White Beeswax 2.5 g Methyl hydroxybenzoate 0.1 g Distilled Water to 100.0 g Heat the Polawax, beeswax and lanolin together at 60°C. Add a solution of methyl hydroxybenzoate. Homogenise using high speed stirring. Allow the temperature to fall to 50°C. Add and disperse the active ingredient. Allow to cool with slow speed stirring. Example D: Lotion for topical use Active Ingredient 1*0 g Sorbitan Monolaurate 0.6 g Polysorbate 20 0.6 g Cetostearyl Alcohol 1.2 g Glycerin 6.0 g Methyl Hydroxybenzoate 0 * 2 g Purified Water B.P. to 100 ml The methyl hydroxybenzoate and glycerin were dissolved in 70ml of the water at 75°C. The sorbitan monolaurate, Polysorbate 20 and cetostearyl alcohol were melted together at 75°C and added to the aqueous solution. The resulting emulsion was homogenised, allowed to cool with continuous stirring and the active ingredient added as a suspension in the remaining water. The whole was stirred until homogeneous. Example E: Oral Tablet (ii) Per tablet Active Ingredient 10.0 mg Lactose 80.0 mg Microcrystalline Cellulose 40.0 mg Povidone 4.0 mg Sodium Starch Glycollate 15.0 mg Magnesium Stearate 1.0 mg Mix together the active ingredient and microcrystalline cellulose before blending with lactose, povidone and sodium starch glycollate. Lubricate with magnesium stearate and compress to produce tablets (150mg per tablet). Example F: Oral capsule Active Ingredient 25.0 mg Starch 1500 100.0 mg Sodium Starch Glycollate 14.0 mg Magnesium Stearate 1.0 mg Mix together the active ingredient, Starch 1500 and sodium starch glycollate before blending with magnesium stearate. Fill power into Size 3 capsule shells (140 mg per capsule). Example G: Powder capsules for inhalation Active Ingredient (0.5-7.0μm powder) 1.0 mg Lactose (30-90μm powder) 49.0 mg The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules (50mg per capsule). Example H: Inhalation aerosol Active Ingredient (0.5-7.0μm powder) 50.0 mg Sorbitan Trioleate 100.0 mg Saccharin Sodium (0.5-7.0μm powder) 5.0 mg Methanol 2.0 mg Trichlorofluoromethane 4.2 g Dichlorodifluoromethane to 10.0 ml The sorbitan trioleate and menthol were dissolved in the trichloro-fluoromethane. The saccharin sodium and active ingredient were dispersed in the mixture which was then transferred to a suitable aerosol canister and the dichlorofluoromethane injected through the valve system. This composition provides 0.5mg of active ingredient in each lOOμl dose. BIOLOGICAL DATA In vitro inhibition of 5-lipoxygenase Leukocytes were isolated from blood donated by normal aspirin-free volunteers by washing and centrifugation. A solution of the test compound in DMSO (lOμl, final concentration 0.01 - lOOμM) was added to the washed cell suspension (480μl) and the mixture incubated at room temperature for 5 minutes. The tubes were placed on ice for 5 minutes and then stimulated with the calcium ionophore A-23187 (lOμl, final concentration 2.0μM) for 5 minutes at 37°C. The reaction was terminated by boiling and the plasma concentration of LTB4 determined by Scintillation Proximity Assay (SPA). Each of the compounds of Synthetic Examples 1-42, when tested in this screen, was found to have an average IC50 of less than 2μM, with the exception of Synthetic Examples 32, 34, 36, 37, 38, 40, 41, and 42 each of which have an IC50 of less than lOμM. In Vitro inhibition of cyclooxygenase Washed platelet suspensions from healthy human donors were prepared according to the method of Radomski et al (Thromb. Res., 30, 383-393, 1983). Tubes containing aliquots (0.5ml) of platelet suspension (10^ cells/ml) were incubated with test drug or vehicle for 5 minutes at room temperature before being placed on an ice bath for a further 5 minutes. The calcium ionophore A-23187 was added (final concentration 2μM) and the tubes were incubated for 5 minutes at 37°C. The reaction was terminated by boiling for 2 minutes and the cellular precipitate removed for centrifugation. The thromboxane B 2 content of the supernatant was determined by radio-immunoassay. Each of the compounds of Synthetic Examples 1 to 4, when tested in this screen, was found to have an average IC50 of less than lOμM SUBSTITUTE SHEET JRULE 2

Claims: CLAIMS 1. A compound of formula (I) OH wherein Y is -C(Q)=C(Q')- ((E)- or (Z)-) wherein Q and Q' are independently selected from hydrogen, Cj_4 alkyl and halo, or Y is -C≡C-; R is Cj_4 alkyl optionally substituted by fluoro; D is Cι_4 alkyl, phenyl or -NR R2 (wherein R! and R2 are independently selected from hydrogen, Cι_4 alkyl, and phenyl); and ring A and ring B are each optionally substituted by a group or groups independently selected from halo, cyano, nitro, hydroxy, Cj_4 alkyl, Cι_4 alkoxy, C 1.4 haloalkyl, C 1.4 haloalkoxy, -C(O)OR 3 , -C(O)R 3 , -C(O)NR 3 R 4 , -NR 3 R 4 , -NHCOR 3 , -NHCO R 3 , -NHC(O)NR 3 R 4 , -NHSO 2 R 3 , -SO 2 NR 3 R 4 (wherein R 3 and R 4 are independently selected from hydrogen, C1-.4 alkyl and phenyl), and -S(O) n R^ (wherein n is an integer of from 0 to 2 and R^ is C1-.4 alkyl, Cβ_\Q aryl (for example, phenyl or naphthyl), or Cg_i2 aralkyl); provided that the compound of formula (I) is not: N-(3-[ 1 , 1 '-biphenyl]-4-yl- 1 -methyl-2-propynyl)-N-hydroxy-urea, N-(3 - [ 1 , 1 '-biphenyl] -4-yl- 1 -methyl-2-propynyl)-N-hydroxy-acetamide, (E)-N-[3-(4'-Cyano-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid, (E)-N-[3-(4*-Fluoro-3-biphenylyl)-l(S)-methyl-2-propenyl]- acetohydroxamic acid, or (E)-N-[3-(4'-Chloro-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; or a salt, solvate, or physiologically functional derivative thereof. 2. A compound of formula (I) according to claim 1 wherein: Y is -C(Q)=C(Q')- (wherein either one of Q and Q' is methyl and the other is hydrogen, or Q and Q' are both hydrogen) or -C≡C-; is Cj_4 alkyl ; D is Cj_4 alkyl, phenyl, or -NH 2 ; Ring A and ring B are optionally substituted by one or two substituents selected from halo, cyano, nitro, Cι_4 alkyl, C1-.4 alkoxy, C1-.4 haloalkyl, and C]_4 haloalkoxy; and Y is attached to ring B at the 3- or 4- position relative to ring A and salts, solvates, and physiologically functional derivatives thereof. 3. A compound according to claim 1 or 2 wherein: Y is (E)- -CH=CH-; R is Cι_4 alkyl; D is Cμ4 alkyl; ring A and ring B are each optionally substituted by one or two groups independently selected from halo, C}_4 alkoxy, and cyano; and Y is attached to ring B at the 3- or 4- position relative to ring A; and salts, solvates and physiologically functional derivatives thereof 4. A compound according to any one of claims 1 to 3 selected from: (E)-N-[3-(4'-fluoro-3-biphenylyl)-l(R)-methyl-2-propenyl]-acetohydroxamic acid; N-[l-(4'-Fluoro-3-biphenylyl)but-l-yn-3(S)-yl]acetohydroxamic acid; (E)-N-[3 '-Cyano-3-biphenylyl)but- 1 -en-3 (S)-yl]acetohydroxamic acid; (E)-N-[3-(3,4'-difluoro-5-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3-(4'-Fluoro-4-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3-(4'-Methoxy-3-biphenylyl)-l(S)-methyl-2-propenyl]acetohydroxamic acid; (E)-N-[3 -(3 '-Fluoro-3 -biphenylyl)- 1 (S)-methyl-2-propenyl] acetohydroxamic acid, (E)- 1 - [3 -(4'-Cyano-3 -biphenylyl)- 1 (R)-methyl-2-propenyl] - 1 -hydroxyurea; (E)- 1 -[( 1 R/S)-3 -(4-Biphenylyl)- 1 -methyl-2-propenyl]- 1 -hydroxyurea; (E)-N-[3-(2 , ,4'-Difluoro-3-biphenylyl)-l(S)-methyl-2-proρenyl]- acetohydroxamic acid; and salts, solvates and physiologically functional derivatives thereof 5. A method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway is indicated; which comprises administration of a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. 6. A method according to claim 5 wherein the clinical condition is selected from asthma, ulcerative colitis, and irritable bowel syndrome. 7. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy. 8. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in the treatment of a medical condition selected from asthma, ulcerative colitis, and irritable bowel syndrome. 9. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic acid metabolic pathway is indicated. 10. A pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrie or excipient, and optionally one or more other therapeutic ingredients. 11. A process for preparing the compounds of formula (I), or salts, solvates, or physiologically functional derivatives thereof which comprises reacting a compound of formula (II) wherein Y, R and the optional substituents on rings A and B are as defined for a compound of formula (I), with a suitable agent or agents to effect conversion of the N-hydrogen to an N-COD group, where D is (a) Cι_4 alkyl or phenyl, or (b) NR1R2 where R! and R^ are as defined in claim 1 ; and optionally (i) separating the mixture of enantiomers so obtained and/or (ii) converting the compound of formula (I) so formed to a corresponding salt, solvate or physiologically functional derivative thereof.

Inventors: HODGSON SIMON TEANBY, WATES PETER JOHN, HODGSON, SIMON, TEANBY, WATES, PETER, JOHN
Applicants: HODGSON SIMON TEANBY, WATES PETER JOHN, WELLCOME FOUND, HODGSON, SIMON, TEANBY, THE WELLCOME FOUNDATION LIMITED, WATES, PETER, JOHN
Application year: 1994
Main classification: C07C259
IPC codes: A61K31, A61P1, A61P3, A61P11, A61P29, A61P43, C07C259, C07C275, C07C311, C07C317, C07C323